Alcohol-LPP3 axis in ischemic stroke

缺血性中风中的酒精-LPP3轴

基本信息

批准号：
9454816
负责人：
Manikandan Panchatcharam
金额：
$ 20.84万
依托单位：
LOUISIANA STATE UNIV HSC SHREVEPORT
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-20 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9454816
关键词：
Address Adult Affect Alcohol consumption Alcoholism Alcohols Antioxidants Applications Grants Arteries Atherosclerosis Binding Biological Models Blood - brain barrier anatomy Cardiomyopathies Cardiovascular Diseases Cause of Death Cerebrovascular Disorders Cerebrovascular system Cerebrum Clinical Cytoskeleton Data Disease Enzymes Event Functional disorder Future Glycerophospholipids Health Heart Heavy Drinking Hydrolysis In Vitro Inflammation Injury Intervention Investigational Therapies Ischemic Stroke Knockout Mice Link Lipids Liver diseases Luciferases Lysophosphatidic Acid Receptors Lysophosphatidylcholines Magnetic Resonance Imaging Mediating Mental disorders Messenger RNA Mitochondria Modeling Mus Near-infrared optical imaging Normal tissue morphology Nuclear Oxidation-Reduction Oxidative Stress Pathway interactions Pharmacology Phosphoric Monoester Hydrolases Play Production Protein Dephosphorylation Proteins Reactive Oxygen Species Regulation Reporter Reporting Rho-associated kinase Role Signal Transduction Source Stroke Superoxide Dismutase System T-Lymphocyte Testing Tight Junctions Transcriptional Regulation United States National Institutes of Health Vascular Diseases alcohol exposure brain endothelial cell cell type cerebrovascular design improved in vivo inhibitor/antagonist inorganic phosphate insight lipid phosphate phosphatase lysophosphatidic acid mimetics novel nuclear factors of activated T-cells offspring oxidant stress problem drinker promoter protective effect response transcription factor viral rescue virtual

项目摘要

Project Abstract Complications of alcoholism such as stroke and cardiomyopathy are leading causes of death among adults. The underlying pathophysiology of these events involves lipids within susceptible arteries leading to subsequent localized inflammation and vascular dysfunction. While the bioactive glycerophospholipid lysophosphatidic acid plays a well-known role in atherosclerotic disease, its role in alcohol-mediated cerebral dysfunction remains virtually unexplored. Lysophosphatidic acid production involves hydrolysis of lysophosphatidylcholine by the secreted enzyme autotaxin, whereas lipid phosphate phosphatase-3 (LPP3) catalyzes lysophosphatidic acid dephosphorylation to generate lipid products that are not receptor active. In this application, we present the first evidence that heavy alcohol consumption (HAC) enhances the cerebrovascular autotaxin levels and decreases LPP3 expression, and this is associated with increased lysophosphatidic acid signaling. Upon HAC, reactive oxygen species (ROS) increases in the cerebrovasculature, whereas the redox-sensitive transcription factor NFAT (a nuclear factor of activated T-cells) has been shown to bind to the autotaxin promoter and induce its expression. Similarly, oxidant stress may deplete LPP3 levels in the context of HAC through reduced LPP3 expression or enhanced LPP3 degradation. Thus, we hypothesize that HAC alters autotaxin and LPP3 expression through ROS production to drive lysophosphatidic acid signaling and cerebrovascular dysfunction. The following interrelated specific aims are designed to provide step-wise and in-depth studies in vitro, in vivo, and in experimental therapeutics settings. Specific aim 1 will assess the role of ROS production in autotaxin expression and lysophosphatidic acid production in the cerebrovasculature following HAC. Specific aim 2 will determine the role of ROS production in LPP3 depletion and LPA production in the cerebrovasculature following HAC. We could identify whether modulation of cellular versus mitochondrial antioxidant status confers a differential protective effect following HAC. Our results should provide specific insight into signaling systems mediated by HAC and may provide novel targets for treatment and might improve cerebrovascular disorders.

项目摘要中风和心肌病等酗酒并发症是成年人死亡的主要原因。这这些事件的潜在病理生理学涉及易感动脉内的脂质，导致随后的局部炎症和血管功能障碍。而具有生物活性的甘油磷脂溶血磷脂酸众所周知，它在动脉粥样硬化疾病中发挥着重要作用，但它在酒精介导的脑功能障碍中的作用仍然存在几乎未经探索。溶血磷脂酸的生产涉及溶血磷脂酰胆碱的水解分泌酶自分泌运动因子，而脂质磷酸磷酸酶 3 (LPP3) 催化溶血磷脂酸去磷酸化产生不具有受体活性的脂质产物。在这个应用程序中，我们提出了第一个有证据表明，大量饮酒（HAC）会增强脑血管自分泌运动因子水平并降低 LPP3 表达，这与溶血磷脂酸信号传导增加有关。 HAC 后，反应性脑血管系统中的氧物种（ROS）增加，而氧化还原敏感转录因子 NFAT（激活 T 细胞的核因子）已被证明可以与自分泌运动因子启动子结合并诱导其产生表达。同样，氧化应激可能会通过减少 LPP3 来消耗 HAC 中的 LPP3 水平表达或增强 LPP3 降解。因此，我们假设 HAC 改变自分泌运动因子和 LPP3 通过产生 ROS 来驱动溶血磷脂酸信号传导和脑血管功能障碍。以下相互关联的具体目标旨在提供逐步深入的体外、体内、以及在实验治疗环境中。具体目标 1 将评估 ROS 产生在自分泌运动因子中的作用 HAC 后脑血管系统中的表达和溶血磷脂酸的产生。具体目标2将确定 ROS 产生在 LPP3 消耗和 LPA 产生中的作用 HAC。我们可以确定细胞抗氧化状态与线粒体抗氧化状态的调节是否会赋予 HAC 后的不同保护作用。我们的结果应该提供对信号系统的具体见解由 HAC 介导，可能提供新的治疗靶点，并可能改善脑血管疾病。